C₆–C₁₀–Dicarboxylic aciduria: Biochemical considerations in relation to diagnosis of β-oxidation defects

Abstract

By means of gas chromatographic methods substantial amounts of the C₆–C₁₀–dicarboxylic acids, i.e. adipic, suberic and sebacic acids, have been found in the urine from children with unexplained attacks of lethargy and hypotonia, presumably related to episodes of fever and/or insufficient food intake. The course have once been fatal and is often characterized by severe hypoglycemia without ketonuria. Systematic gas chromatographic/mass spectrometric determinations of seleted organic acid metabolites in the urine, together with enzymatic measurements in fibroblasts and clinical data from 4 patients of this category, have shown that the biochemical basis of this syndrome can be inborn errors of the β-oxidation of fatty acids, localized to the medium-chain acyl-CoA dehydrogenation system.

The biosynthesis of adipic, suberic and sebacic acids was studied using ketotic rats as the model, since ketosis in rats and humans is accompanied by excessive urinary excretion of adipic and suberic acids. A probable pathway for the production of the three dicarboxylic acids was found to be an initial ω-oxidation of the medium-chain C₁₀–C₁₄–monocarboxylic acids followed by β-oxidation of the resulting medium-chain dicarboxylic acids. It is argued that the source of the ω-oxidizable monocarboxylic acids in ketosis most probaly is the fat deposites, and it is speculated that the patients with β-oxidation defects supplement this source with β-oxidation intermediate medium-chain monocarboxylic acids, accumulated as a result of the defect.

The ratio between the excreted amounts of adipic acid and sebacic acid in the urine from the patients with β-oxidation defects is < 50. This is in contrast to the ratio in urine from ketotic patients, where it is > 100.

Adipic acid/sebacic acid ratio — measured by means of a gas chromatographic analysis — is therefore suggested as a tool in the diagnosis of dicarboxylic acidurias. Based on the clinical picture and the pattern of a serie of organic acids in the urinary metabolic profile our four patients can be divided in two types of dicarboxylic aciduria. The two types have different therapeutic implications.

Key words:

• C₆–C₁₀–dicarboxylic aciduria
• β-oxidation defects
• hexanoylglycine
• 5-OH-hexanoic acid
• ethylmalonic acid